The mammalian touch-sensing afferents, A? low-threshold mechanoreceptors (LTMRs), have long been pro- posed to be important players in modulating nociceptive pathways. However, the exact roles of A? LTMRs in chronic pain are still under debate. Aiming to incorporating the known anatomy of A? LTMRs and existing con- flicting results, we hypothesize that in chronic pain conditions, peripheral activation of A? LTMRs innervating the affected region triggers pain through dis-inhibited feedforward circuits, whereas dorsal column activation recruits A? LTMRs innervating both affected and non-affected regions, which could block activities of affected A? LTMRs and/or pain pathways through lateral inhibition. To specifically test this idea, we will generate transgenic mice in which channelrhodopsin will be specifically expressed in A? LTMRs and examine their histology (Aim 1a) and physiological properties (Aims 1b) at base-line and chronic pain conditions. We will then take advantage of the spatial and temporal precision of optogenetics and stimulate A? LTMRs peripherally in the skin or centrally in the spinal cord dorsal column at baseline and various chronic pain conditions to compare their behavioral outcomes (Aim 2). Finally, we will use spinal cord slice recordings to elucidate the underlying circuit mechanisms (Aim 3). We will combine dorsal root electrical stimulation and optical stimulation to activate A? LTMRs locally from a given level or broadly to determine lateral inhibition existing among A? LTMRs at baseline and chronic pain conditions. We will also determine whether this lateral inhibition could modulate the local nociceptive circuits affected by chronic inflamma- tion/injury. Collectively, our results are expected to establish a new model of how crosstalk between modalities (touch and nociceptive pathways) and within one modality (A? LTMRs from different spinal cord segments) work together to modulate pain sensation. This model would not only explain the complicated functions of A? LTMRs in chronic pain but also provide novel insights for pain pathway intervention in the future. Our assem- bled team is well suited to complete these aims, utilizing combined expertise in mouse genetics and A? LTMRs (PI Luo) and physiology and computational neuroscience with the mammalian somatosensory system (co- investigator O?Connor).